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Ann Thorac Surg 2005;80:1033-1039
© 2005 The Society of Thoracic Surgeons

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Original article: General thoracic

Alcohol Abuse Predicts Progression of Disease and Death in Patients with Lung Cancer

^a Department of Surgery, Department of Veterans Affairs Medical Center, Dayton, Ohio
^b Department of Hematology and Oncology, Department of Veterans Affairs Medical Center, Dayton, Ohio
^c Department of Radiation Oncology, Department of Veterans Affairs Medical Center, Dayton, Ohio
^d Department of Surgery, Wright State University School of Medicine, Dayton, Ohio
^e Department of Hematology and Oncology, Wright State University School of Medicine, Dayton, Ohio

Accepted for publication March 18, 2005.

^_* Address reprint requests to Dr Paull, Wright State University School of Medicine, Department of Surgery, No. 112, VA Medical Center, 4100 W Third St, Dayton, OH45428 (Email: douglas.paull{at}wright.edu).

	Abstract

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BACKGROUND: Few studies have examined long-term outcomes in alcohol-abusing patients with lung cancer. The purpose of this study was to examine the effect of alcohol abuse on the prognosis of patients with lung cancer.

METHODS: The study was composed of 114 consecutive patients with nonsmall-cell lung cancer treated at a Department of Veterans Affairs Medical Center. An alcohol-abusing group consisted of 36 patients with one of the following at the time of lung cancer diagnosis: positive screening questionnaire, alcohol consumption more than 5 drinks or cans of beer a day, or criteria for a diagnosis of alcohol dependence/abuse according to the Diagnostic and Statistical Manual for Mental Disorders IV. The comparison group consisted of 78 nonabusing patients.

RESULTS: Alcohol abusers, compared with nonabusers, had worse Kaplan-Meier overall survival (median 8.5 versus 17.5 months, p = 0.05) and progression-free survival (median 6.0 versus 15.5 months, p = 0.04). In multivariate analyses including alcohol abuse, Charlson comorbidity, pack-years smoking, performance status, and stage, only stage of disease, performance status, and alcohol abuse (odds ratio = 3.44, 95% confidence interval = 1.17 to 10.1, p = 0.02) predicted progression of disease or death within 12 months of diagnosis. Alcohol abuse was also an independent predictor of disease-specific survival (hazard ratio = 1.65, 95% confidence interval = 1.01 to 2.80, p = 0.05) and progression-free survival (hazard ratio = 1.79, 95% confidence interval = 1.12 to 2.86, p = 0.01) among patients with lung cancer.

CONCLUSIONS: Alcohol-abusing patients with nonsmall-cell lung cancer have worse outcomes than nonabusing patients. The adverse prognosis associated with alcohol abuse is independent of comorbidity, performance status, or smoking history.

	Introduction

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Lung cancer is the leading cause of cancer death in men and women in the United States, accounting for 160,000 cancer deaths a year [1]. The Department of Veterans Affairs (VA) is the largest provider of substance abuse treatment in the United States where as many as 36% of patients are treated for an alcohol-related disorder [2]. Furthermore, alcohol users are more likely to smoke compared with nondrinkers [3]. Therefore, the presence of lung cancer requiring treatment in an alcohol-abusing patient is not rare.

Heavy alcohol use has been shown to adversely affect survival in a variety of malignancies [4, 5]. Despite reports of more than 160 prognostic variables affecting lung cancer outcomes, few studies have examined alcohol abuse as an independent prognostic indicator [6, 7]. The confounding variables of smoking and comorbidity complicate any study of alcohol abuse and lung cancer survival.

Previous studies of lung cancer and alcohol abuse have demonstrated an increase in the morbidity and mortality for surgical resection of early stage lung cancer [8, 9]. Unfortunately, most patients with lung cancer have advanced stage, unresectable disease at the time of diagnosis [10]. Few studies have examined long-term outcomes in alcohol-abusing lung cancer patients. The purpose of the current study was to examine any long-term outcome differences between alcohol abusers and nonabusers with lung cancer.

	Material and Methods

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One hundred fourteen consecutive patients with biopsy proven nonsmall-cell lung cancer (NSCLC), all stages, were entered into the study. This was a retrospective study including every patient undergoing bronchoscopy, mediastinoscopy, mediastinotomy, thoracoscopy, or thoracotomy for diagnosis, staging, or treatment at a single VA thoracic clinic from 1998 to 2003. The study was approved by the Wright State University School of Medicine Institutional Review Board on November 7, 2003. The results of any current CAGE alcohol abuse screening test was extracted from the computerized medical record. (The acronym CAGE is derived from these questions: Have you ever felt you should Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt Guilty about your drinking? Have you ever had a drink first thing in the morning [Eye-opener]?) The patient’s social history was reviewed for daily alcohol consumption.

Patients were assigned to one of two groups depending on alcohol use at the time of lung cancer diagnosis. Lung cancer patients were placed in the alcohol-abusing group (Etoh group, n = 36) if they had one or more of the following criteria present at the time of lung cancer diagnosis: (1) CAGE screening score of 2 or more; (2) alcohol consumption of 5 or more drinks or beers a day; or (3) satisfied criteria for a current diagnosis of alcohol dependence/abuse (303.90, 305.00) according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV). Nonabusers (Non-etoh group, n = 78), did not share any of these three defining characteristics. Patients with a distant history of alcohol abuse were placed in the Non-etoh group unless they possessed one of the three defining features of current abuse at the time of lung cancer diagnosis. All patients were assigned to either the Etoh or Non-etoh groups prior to extraction of detailed clinical data involving the diagnosis, staging, treatment, and outcome of their lung cancer.

Clinical data were extracted from the computerized medical record and entered into an Excel spreadsheet (Microsoft, Bellevue, Washington) by one author (D.E.P.). Data included age, sex, smoking history, comorbidity, Eastern Cooperative Group (ECOG) performance status, history of other aerodigestive tumors, liver enzymes, hepatitis profile, hematologic studies, pulmonary function, histology, stage, type of treatment, progression/recurrence, and survival. Socioeconomic information including marital and occupational status and any current psychiatric or drug abuse problems were included from the medical record. Response to treatment was assessed from careful review of clinical notes and serial radiographic studies by a thoracic surgeon, medical oncologist, and radiation oncologist (D.E.P.,M.A.B., H.W.C.). Final closeout for follow-up was the status of the patient at the last clinic visit recorded as of January 1, 2005. Follow-up averaged 20.3 ± 1.8 months (range, 1 to 77) with no significant difference between Etoh and Non-etoh groups. Charlson comorbidity [11] and ECOG performance scores [12] were determined. Patients were awarded 1 point for liver disease if they had elevated liver function tests: gamma glutamyl transferase (GGT) greater than 94 U/L, or serum glutamate oxaloacetate transferase (SGOT) greater than 40 U/L, or both.

Survival curves were constructed by the Kaplan-Meier method. Overall survival, disease-specific survival and progression-free survival were calculated from the date of tissue diagnosis of lung cancer to the date of death from any cause, death from lung cancer, or progression of disease, respectively. For patients with early stage disease, progression of disease was defined as any recurrence after resection. In unresectable patients with advanced disease undergoing chemotherapy or radiation, or both, progression was defined according to the National Cancer Institute standards as a 20% increase in the size of targeted, measurable lesions or the development of any new lesions [13]. Response to chemotherapy and chemotherapy toxicity was graded according to published National Cancer Institute guidelines [13, 14]. Based on measurements of serial radiographic studies, patients receiving chemotherapy had a "best response" that was either progressive disease, stable disease, partial response, or complete response.

Statistical analysis was performed by importing the Excel datafile into the NCSS/PASS 2000 (NCSS Statistical Software, Kaysville, Utah) and InStat (Graphpad, San Diego, California) statistical software programs. A two-tailed Fisher exact test compared discrete data between Etoh and Non-etoh groups. Continuous data were compared using an unpaired, two-tailed Student t test, or the Mann-Whitney U test, and reported as the mean ± standard error. In an effort to minimize type I error, the Bonferroni method of sequential analysis was utilized to correct p values for multiple comparisons between Etoh and Non-etoh groups. Survival curves between the two groups of patients were compared using the Gehans-Wilcoxon log-rank tests. A Cox proportional hazards regression was established using the five variables of alcohol abuse, Charlson comorbidity score, ECOG performance status, pack-years smoking, and stage of disease to predict overall, disease-specific, and progression-free survival. A logistic regression utilized the same variables to predict the event of either death or progression of disease within 12 months of diagnosis. Hazard ratio (HR) and odds ratio (OR) are reported with 95% confidence intervals (CI). A p value of 0.05 or less was considered significant, a p value greater than 0.05 was not significant (NS). In both the Cox proportional hazard and multiple logistic regression, there were more than 50 outcome events, with the five predictor variables satisfying the customary 10:1 ratio of events:variables for such models.

	Results

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The clinical characteristics of the 114 patients with NSCLC in this study are presented in Table 1. Among the 36 abusers, 2 of 36 (6%) were identified by a positive CAGE questionnaire, 17 of 36 (47%) by current level of alcohol consumption, and 17 of 36 (47%) because of current DSM IV criteria for alcohol abuse/dependence. The type of alcohol consumed by abusers was solely beer in 17 of 36 patients (47%), hard liquor in 7 of 36 (20%), and either a mixture of beer and hard liquor or unspecified in 12 of 36 patients (33%).

Kaplan-Meier overall survival (median 8.5 versus 17.5 months, p = 0.05) and progression-free survival (median 6.0 versus 15.5 months, p = 0.04) was worse for Etoh patients compared with Non-etoh patients (Fig 1). Survival analysis by alcohol abuse status for each of stage of disease was hampered by small numbers in such subsets. For the largest group, 51 patients with stage III disease, Etoh patients had distinctly worse overall survival and progression-free survival compared with Non-etoh patients (Fig 2). Overall median survival, Etoh versus Non-etoh patients, respectively, by stage was as follows: I and II (28 versus 27.5 months, p = 0.27); III (5.0 versus 12 months, p = 0.03); and IV (6.0 versus 5.0 months, p = 0.50). Median progression-free survival by stage, Etoh versus Non-etoh, was as follows: I and II (17.5 versus 23.5 months, p = 0.36); III (5.0 versus 9.0 months, p = 0.02); and IV (5.0 versus 3.0 months, p = 0.65).

View larger version (10K): [in this window] [in a new window]   Fig 1. (A) Overall survival of 36 alcohol-abusing patients (Etoh; broken line) and 78 nonabusing patients (Non-etoh; solid line) with nonsmall-cell lung cancer (NSCLC). aMedian survival in months (95% confidence intervals). bGehans-Wilcoxon log-rank test. Error bars ± SEM. (B) Progression-free survival of 36 alcohol-abusing patients (Etoh; broken line) and 78 nonabusing patients (Non-etoh; solid line) with NSCLC. aMedian survival in months (95% confidence intervals). bGehans-Wilcoxon log-rank test. cProgression = 20% increase in size of measurable disease or any new lesions. Error bars ± SEM.

View larger version (10K): [in this window] [in a new window]   Fig 2. (A) Overall survival of 18 alcohol-abusing patients (Etoh; broken line) and 33 nonabusing patients (Non-etoh; solid line) with stage III nonsmall-cell lung cancer (NSCLC). aMedian survival in months (95% confidence intervals). bGehans-Wilcoxon log-rank test. Error bars ± SEM. (B) Progression-free survival of 18 alcohol-abusing patients (Etoh; broken line) and 33 nonabusing patients (Non-etoh; solid line) with stage III NSCLC. aMedian survival in months (95% confidence intervals). bGehans-Wilcoxon log-rank test. cProgression = 20% increase in size of measurable disease or any new lesions. Error bars ± SEM.

As expected, in multivariate analyses, ECOG performance status and stage of disease were strong predictors of all outcomes in patients with lung cancer. However, alcohol abuse, even when adjusted for comorbidity and smoking, was a significant independent predictor of disease-specific survival, progression-free survival, and death or progression of disease within 12 months (Table 2). There was no significant association between the variable alcohol abuse and either ECOG performance status or stage of disease. There was, however, a strong correlation between stage of disease and ECOG performance status (regression coefficient = 0.51, p = 0.000).

Thirteen of 14 Etoh patients (93%) and 29 of 39 Non-etoh patients (74%) undergoing chemotherapy for stage III or IV disease had sufficient information to determine the level of response accurately. Total paclitaxel doses (Etoh 456 ± 101 mg/M² versus Non-etoh 509 ± 59 mg/M², p = NS) and carboplatin doses (Etoh 1,128 ± 209 mg/M² versus Non-etoh 926 ± 113 mg/M², p = NS) were similar. There was a trend toward greater chemotherapy toxicity, represented as grade 2 to 4 granulocytopenia, in Etoh patients (6 of 13, 46%) compared with Non-etoh patients (8 of 29, 28%; p = NS). Only 3 of 13 Etoh patients (23%) compared with 17 of 29 Non-etoh patients (59%) had either a partial or complete response as the best response to chemotherapy (p = 0.05). The importance of this latter finding was reinforced by Kaplan-Meier survival differences of chemotherapy responders versus nonresponders. Median survival was 16.5 months and 6 months for responders and nonresponders, respectively (p = 0.003).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The definition of current alcohol abuse used in our study was based on criteria suggested in previous studies of alcohol-abusing patients, including VA patients and patients with lung cancer [9, 15]. Chronic and excessive alcohol intake is associated with an increased incidence of a variety of cancers including liver, oral cavity, esophagus, colorectal, and breast [16]. The relationship between alcohol intake and the development of lung cancer is less clear. Several studies have shown that when adjusted for smoking, light to moderate drinking is not associated with an increased incidence of lung cancer [17, 18]. Moderate wine drinking may even be protective [19]. Excessive drinking, as in our study, may be associated with an increased risk of lung cancer [19–21].

The two strongest predictors of survival in NSCLC patients in this study were the the ECOG performance status and stage of the disease of the patient at the time of diagnosis. Previous, multivariate studies confirm the strong association between stage of disease and ECOG performance status and overall survival, disease-free survival, and response to therapy among lung cancer patients [22, 23]. The most important new finding in this study was that alcohol abuse, as defined, was significantly and independently associated with worse outcomes among patients with NSCLC.

Previous studies have linked alcohol abuse only secondarily to a poor prognosis in lung cancer, attributing the effect to increased smoking or comorbidity in abusing patients [7]. In the current multivariate analysis, alcohol abuse remained a significant predictor of outcomes, even when adjusted for Charlson comorbidity scores and pack-years smoking. It has been argued that Charlson comorbidity is a better predictor of outcomes in tumors with a long natural history, such as prostate cancer, where patients may die of other causes [24]. The majority of patients with lung cancer present with stage III or IV disease, with relatively short survival, and Charlson comorbidity may not be as strong a predictor. Other studies have demonstrated contradictory results regarding Charlson comorbidity and lung cancer survival [1, 25].

Pack-years smoking and pulmonary function were similar between Etoh and Non-etoh groups in the current study. Pack-years smoking did not predict overall or progression-free survival in either univariate or multivariate analyses. Other studies have demonstrated that smoking history is either associated with no effect or worse survival in patients with lung cancer [1, 23, 26, 27]. However, the current study does not exclude smoking as a contributing factor to the worse prognosis among alcoholic patients with NSCLC. We did not examine smoking habits after diagnosis and throughout treatment. Current and persistent smoking may be related to a worse quality of life and worse survival in lung cancer patients [28].

Alcohol abuse increases the morbidity and mortality of pulmonary resection for early stage lung cancer [8, 9]. Postoperative deaths of alcohol-abusing lung cancer patients are due to an increase in respiratory and infectious complications [8]. Survival differences between Etoh and Non-etoh groups were limited to stage III patients in the current study. It is possible that this finding was simply a reflection of greater numbers of patients in the subset stage III compared with other stages. Larger studies may yet demonstrate worse long-term outcomes for Etoh patients in earlier stages of disease. Nonetheless, our study demonstrated a number of factors which could lead selectively to worse outcomes among alcohol-abusing patients with stage III lung cancer including (1) worse response rates to chemotherapy, (2) smaller radiation doses delivered, (3) less multimodality treatment, and (4) noncompliance.

There remains the possibility that the effect of alcohol abuse on survival is not simply a function of smoking history, comorbidity, or compliance. Possible explanations would include more biologically aggressive tumors or impaired host defense in alcoholic lung cancer patients. Alcohol drinkers with lung cancer have an increased incidence of p53 genetic mutations in their tumors [29]. Furthermore, lung cancer patients with p53 mutations have a worse prognosis than wildtype patients [30]. These mutations may be due to poor hepatic clearance of carcinogens or alternatively the formation of acetaldehyde with resultant inhibition of DNA repair in alcohol users with lung cancer [30]. Such an effect would seem even more likely in alcohol abusers than alcohol users.

Alcohol abuse, even in the absence of overt clinical liver disease, initiates important immunologic impairments including depressed numbers and function of T cells and neutrophils as well as altered cytokine production [31, 32]. In laboratory tumor-bearing animal models, alcohol consumption leads to tumor progression by suppressing natural killer cell activity against cancer cells [33, 34]. Human lung cancer cell lines’ ability to metastasize in animal models is highly dependent on natural killer cell activity [35].

Since the alcohol-abusing patient with lung cancer is at increased risk of perioperative morbidity and mortality, and appears to have worse long-term outcomes, identification of such patients in thoracic oncology clinics is crucial. Once the alcoholic with NSCLC is identified, efforts focus on alcohol and smoking cessation. Past alcohol problems do not necessarily predict the inability to stop smoking [36]. High-dose nicotine patches are effective for smokers with a history of alcohol abuse [37]. Smoking cessation may enhance alcohol abstinence [38]. For preoperative patients, we prefer a supervised setting including brief intervention, smoking cessation, and abstinence. There are data that perioperative morbidity and mortality improve in abstinent patients [39, 40]. Such efforts may possibly improve outcomes and quality of life in the alcohol-abusing patient diagnosed with lung cancer.

	Acknowledgments

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The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or Wright State University.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Douglas E. Paull Alex G. Little Samuel A. Adebonojo Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paull, D. E. Articles by Adebonojo, S. A. Search for Related Content PubMed PubMed Citation Articles by Paull, D. E. Articles by Adebonojo, S. A. Related Collections Lung - cancer